9-10 Ethanoanthracene derivatives

ABSTRACT

The maleic acid adduct of anthracene is used as a starting material for 11-amino-12-carboalkoxy-9,10-dihydro-9,10-ethanoanthracene, which through reaction with nitrous acid in a protic solvent provides an 11-substituted-12-carboalkoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene which is then converted into the useful intermediate 12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.

RELATED APPLICATIONS

This is a division of Application Ser. No. 578,725, filed May 19, 1975,now U.S. Pat. No. 4,104,475, which is a division of Application Ser. No.371,118, filed June 8, 1973, now U.S. Pat. No. 3,950,407.

BACKGROUND OF THE INVENTION

The compound12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene (I) isa known intermediate compound in a process for preparation ofpharmacologically active 10,11-dihydro-12-(substitutedaminoalkyl)-5,10-methano-5H-dibenzo[a,d]-cycloheptenes. (See U.S. patentapplication Ser. No. 194,056 or German Offenlegungschrift No.2,216,884.) The novel route of this invention for preparing thisvaluable intermediate employs several novel intermediates.

References useful to show the state of the art include S. Wawzonek etal, J. Org. Chem. 18, 288 (1953); W. R. Vaughan et al, J. Am. Chem. Soc.80, 1956 (1958); C.A. 61, 6971f, thesis of D. E. Plorde and C.A. 61,14551, thesis of J. Mohrig.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the process wherein12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene(Compound I) is first prepared and the intermediate is used forpreparation of 10,11-dihydro-12-(substitutedaminoalkyl)-5,10-methano-5H-dibenzo[a,d]cycloheptenes having the desiredsubstituents and structural configuration. Compound (I) is prepared bytreating the maleic anhydride adduct of anthracene to make the novelintermediate 11-amino-12-carboalkoxy-9,10-dihydro-9,10-ethanoanthracenein a procedure involving several steps, from which, in two steps byreaction with nitrous acid in a protic solvent, is prepared an11-substituted-12-carboalkoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptenewhich is then converted to compound (I). Compound (I) can be prepared ineither the syn or anti isomeric forms, and the routes to each are shownin the sequence of reactions set forth in the accompanying drawing, FIG.1, wherein R represents lower alkyl and R' represents hydrogen, loweralkyl or lower acyl. "Lower" herein means having 1 to 6 carbon atoms andis preferably 1 to 3 carbon atoms.

The starting material for the process, the maleic anhydride adduct ofanthracene, is known to the art, as are the cis and trans acid esters IIand III and the lactone X. The other intermediate compounds produced inthis process are shown in the reaction sequence are novel and comprise apart of the present invention.

When the maleic anhydride adduct of anthracene (which also can be termed11,12-cis-dicarboxy-9,10-dihydro-9,10-ethanoanthracene) is reacted toproduce the carboalkoxy ester-carboxy compound, it can be made to formthe trans compound (II) or the cis compound (III) depending upon thereaction conditions. When the anhydride is treated with a lower alkanolin the presence of a strong base such as an alkali metal alkoxide, forexample sodium methoxide or ethoxide as shown in step a, at atemperature of about 0° to 120° C. and preferably from about 20° to 90°C., the product isolated is the trans isomer. When heated in a loweralkanol such as methanol, ethanol or n-butanol as shown in step b, at atemperature of about 60° to 120° C., a cis ester of formula II isformed. Using the resulting cis- ortrans-12-carboalkoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthracenecompounds of formula II or formula III, respectively, the carboxy groupis (1) reacted with a lower alkyl chloroformate such as ethylchloroformate in the presence of a strong base, such as triethylamine,trimethylamine, pyridine, N,N-dimethylaniline and the like, in an inertsolvent such as acetone, benzene, chloroform, acetonitrile and the like,at a temperature of about -20° to 10° C., to provide the mixed anhydridederivative which is not isolated. The mixed anhydride derivative is (2)treated with aqueous sodium or potassium azide at a temperature of -20°to 25° C. to form the acyl azide derivative (generally a solid) which isfurther reacted (3) by heating at about 80° to 120° C. in an inertsolvent such as toluene to give a rearrangement intermediate isocyanate.The isocyanate is (4) treated with benzyl alcohol at about 80° to 120°C. to provide a trans- orcis-11-(N-carbobenzyloxyamino)-12-carboethoxy-9,10-dihydro-9,10-ethanoanthracenecompound of formula IV or V. The products of these steps need not beisolated and purified. It will be apparent that in the case of the azideit is removed from the reaction mixture in which it was formed, as byfiltration.

The compound of formula IV or V is debenzylated by catalytichydrogenation as shown in step (5). An inert solvent is convenientlyused, for example ethyl acetate, methanol, ethanol and acetic acid. Thepreferred hydrogenation catalyst is palladium on charcoal. Thetemperature is generally about 25° C. but may range up to 100° C. toincrease the rate of reaction. The product obtained is the keyintermediate, trans- orcis-11-amino-12-carboalkoxy-9,10-dihydro-9,10-ethanoanthracene offormula VI or VII.

The compound of formula VI or VII is (6) reacted with nitrous acid in aprotic solvent such as an alkanoic acid, e.g. acetic acid, propionicacid, trifluoroacetic acid or n-butyric acid, an alcohol, e.g. methanol,ethanol or propanol, or an inorganic acid, e.g. aqueous hydrochloricacid or dilute sulfuric acid. The reaction temperature is between about0° and 50° C. If an inorganic acid is used, or water is present, thesubstituent in the 8-position of the rearranged product will generallyby hydroxy. It is presently preferred to use a lower alkanoic acid suchas acetic acid or propionic acid as the solvent. Rearrangement to acycloheptene structure occurs, and the rearrangement product is a11-lower acyloxy-12-anti- or syn-lowercarboalkoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptenecompound of formula VIII or IX wherein R' is hydrogen, lower alkyl orthe acyl residue of an alkanoic acid.

The compound of formula VIII or IX is (7) catalytically reduced toremove the substituent from the 11-position. This reduction is generallycarried out in an inert solvent, such as acetic acid, ethyl acetate andthe like. The preferred catalyst is palladium on charcoal. Thetemperature is generally about 25° C., but may range up to 100° C. Acatalytic amount of 70 percent perchloric acid is used. The carboxylicacid ester in the 12 position is then (8) saponified at 80° to 120° C.to complete the transformation. General saponification methods known tothe art are used, preferably simple hydrolysis using aqueous alkalimetal hydroxide such as sodium hydroxide. The product is the syn or antiisomer of compound I,12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene,depending on the starting compound employed.

As an alternative method useful in the case of the preparation of syncompounds, which provides higher yields and easier purification,compound IX may be (9) converted to the corresponding known lactone byfirst removing the R' substituent in the 11-position, then cyclizing.This is done by first heating at about 25° to 100° C. with aqueousinorganic base, for example 10 percent sodium hydroxide, to provide thehydroxy acid. (When R' is alkyl it may be advantageous to cleave thegroup to hydroxyl form by routine ether cleavage methods, such astreatment with aqueous hydroiodic acid at temperatures in the range of25° to 100° C., since the alkoxy group will not be cleaved by base. Thisstep is equivalent to using compound in which R' is hydrogen). Theintermediate hydroxy acid is then converted to the lactone X by heatingat about 70° to 120° C. in an inert solvent such as toluene in thepresence of a catalytic amount of an acid such as p-toluene sulfonicacid. The lactone X is (10) reduced catalytically as in step (7) ininert solvent solution, preferably using palladium on charcoal, tocomplete the conversion to syn formula I compound. An inert solvent suchas ethyl acetate is preferred.

The compound of formula I, whether in the syn or anti form, is suitablefor further reaction as described in the art to provide thepharmacologically active 10,11-dihydro-12-(substitutedaminoalkyl)-5,10-methano-5H-dibenzo[a,d]cycloheptenes and their salts.

The following examples are provided to illustrate the process of theinvention and preparation of the novel intermediate compounds of theinvention and their salts, and are not intended to be limiting of theinvention described hereinabove.

EXAMPLE 1

A fresh batch of sodium ethoxide is prepared by reaction of 14 g. ofsodium and 300 ml. of ethanol. To this solution is added in one batch 70g. (0.253 mole) of11,12-cis-dicarboxy-9,10-dihydro-9,10-ethanoanthracene anhydride, andthe mixture is stirred for 20 hours at about 25° C. The resultingsolution is poured into 1.3 liters of ice water containing 100 ml. ofconcentrated hydrochloric acid. An oil separates and solidifies. Thesolid is separated by filtration, washed with water and dried to provide72.7 g. oftrans-12-carboethoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthracene, m.p.182°-184° C.

Analysis: Calculated for C₂₀ H₁₈ O₄ : %C, 74.5; %H, 5.63. Found: %C,74.5; %H, 5.80.

EXAMPLE 2

A mixture of 1.5 liters of methanol and 70.5 g. (0.255 mole) of11,12-cis-dicarboxy-9,10-dihydro-9,10-ethanoanthracene anhydride isheated at its reflux temperature for 21 hours. The mixture is evaporatedunder vacuum, and hexane is added to the residue. The residual oilslowly crystallizes, and the solid is separated by filtration to provide61.1 g. of the known compoundcis-12-carbomethoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthracene.

EXAMPLE 3

A solution oftrans-12-carboethoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthraceneprepared as set forth in Example 1 (19.3 g., 60 mmoles) in 11 ml. ofwater and 100 ml. of acetone is cooled to 0° C. Ethyl chloroformate (8.6g., 79 mmoles) in 30 ml. of acetone is added dropwise at 0° C., then themixture is stirred at 0° C. for about thirty minutes. Sodium azide (6.2g., 94 mmoles) in 20 ml. of water is added at 0° C., and the mixture isstirred at 0° C. for one hour, then poured into 500 ml. of ice water.The product is extracted twice with diethyl ether, the ether layers arewashed with saturated sodium chloride solution, then dried overanhydrous magnesium sulfate. Evaporation under vacuum gives 19.7 g. of awhite solid,trans-11-azido-12-carboethoxy-9,10-dihydro-9,10-ethanoanthracene. Theinfrared spectral analysis of this compound is in agreement with theassigned structure. The solid azide is dissolved in 75ml. of dry tolueneand heated on a steam bath until the evolution of nitrogen stops. Thetoluene is removed by evaporation under vacuum to provide 16.9 g. of ayellow oil. The oil is treated with 17.2 g. of benzyl alcohol, and themixture is heated on a steam bath for two hours. The excess benzylalcohol is removed by evaporation under vacuum leaving 22.7 g. of ayellow oil,trans-11-(N-carbobenzyloxyamino)-12-carboethoxy-9,10-dihydro-9,10-ethanoanthracene.The oil dissolved in 100 ml. of ethyl acetate, 5.0 g. of palladium oncharcoal are added and the mixture is treated with hydrogen gas at about45 psi on a Parr apparatus until uptake of hydrogen stops. The mixtureis filtered, the filtrate is evaporated under vacuum, and the residue isdissolved in diethyl ether. The ether solution is washed with saturatedsodium bicarbonate solution and saturated sodium chloride solution, thendried over anhydrous magnesium sulfate to give 20.7 g. of an oil. Theoil is dissolved in diethyl ether and extracted with 5 percenthydrochloric acid. The acid extracts are neutralized with sodiumbicarbonate. The aqueous solution is extracted with diethyl ether, andthe ether layer is dried over magnesium sulfate. The ether is removed byevaporation under vacuum to provide a solid residue which isrecrystallized from a benzene-hexane mixture to providetrans-11-amino-12-carboethoxy-9,10-dihydro-9,10-ethanoanthracene, m.p.118°-121° C.

Analysis: Calculated for C₁₉ H₁₉ NO₂ : %C, 77.8; %H, 6.53; %N, 4.78.Found: %C, 78.1; %H, 6.50; %N, 4.70.

EXAMPLE 4

Using the method of Example 3, but starting withcis-12-carbomethoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthracene, theintermediatecis-11-(N-carbobenzyloxyamino)-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene,m.p. 131°-134° C. (Analysis: Calculated for C₂₆ H₂₃ NO₄ : %C, 75.4; %H,5.6; %N, 3.4; Found: %C, 75.4; %H, 5.8; %N, 3.3.), is prepared and isfurther reacted as in Example 3 untilcis-11-amino-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene (m.p.171°-174° C.) is obtained. When this product is dissolved in diethylether and treated with a solution of hydrogen chloride in isopropanol, awhite solid is obtained which is recrystallized from isopropanol.Nuclear magnetic resonance spectral analysis supports the structuralassignment of the carefully dried solid product,cis-11-amino-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracenehydrochloride, m.p. 207°-208° C.

Analysis: Calculated for C₁₈ H₁₇ NO₂ HCl: %C, 68.5; %H, 5.75; %N, 4.4.Found: %C, 68.1; %H, 5.90; %N, 4.3.

Other acid addition salts of this 11-amino derivative (or thecorresponding trans compound), such as the acetate, sulfate, nitrate,propionate, etc., are readily formed by treating the base with equimolaramounts of the selected acid, as is well known to the art, in a suitablevolatile solvent, followed by removal of the solvent as by evaporation.

EXAMPLE 5

To a solution oftrans-11-amino-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene (19.3g., 69.1 mmoles) in 75 ml. of acetic acid is added 14.4 g. of sodiumnitrite (208.5 mmoles) in small portions over two hours, maintaining thetemperature below about 50° C. The mixture is then stirred for aboutsixteen hours at about 25° C. The mixture is evaporated under vacuum toremove acetic acid, and water and dichloromethane are added. The layersare separated, and the dichloromethane layer is washed with 2Nhydrochloric acid, saturated sodium bicarbonate solution and saturatedsodium chloride solution, then dried over anhydrous magnesium sulfate.Evaporation under vacuum provides an oil which is dissolved in 10 ml. ofpyridine and 40 ml. of acetic anhydride by heating on a steam bath thenallowed to stand at about 25° C. for one day. The mixture is evaporatedunder vacuum, then water and dichloromethane are added to the residue.The layers are separated, and the dichloromethane layer is washed with 2N hydrochloric acid, saturated sodium bicarbonate solution and saturatedsodium chloride solution, then dried over anhydrous magnesium sulfate.Evaporation under vacuum provides 19.4 g. of solid, recrystallized froma benzenehexane mixture to give a product, m.p. 124°-135° C. Anotherrecrystallization is carried out from benzene, then thorough dryinggives m.p. 139°-141° C. for11-exo-acetoxy-12-anti-carbomethoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.Nuclear magnetic resonance and infrared spectral analysis confirm thestructure.

Analysis: Calculated for C₂₀ H₁₈ O₄ : %C, 74.5; %H, 5.6. Found: %C,75.2; %H, 5.5.

EXAMPLE 6

Using the method of Example 5,cis-11-amino-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene isconverted by reaction with nitrous acid in acetic acid to11-acetoxy-syn-12-carbomethoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.This product is a mixture of exo and endo isomers at the 11 position.However, this product can be used without further purification asdescribed in Example 9.

EXAMPLE 7

To a solution ofexo-11-acetoxy-2-anti-carbomethoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene(1.1 g.) in 50 ml. of acetic acid is added 0.5 g. of 10 percentpalladium on charcoal and two drops of 70 percent perchloric acid. Themixture is treated with hydrogen gas at 50 psi at room temperature on aPaar apparatus for about eighteen hours. The mixture is filtered, andthe filtrate is evaporated under vacuum to provide a solid residue. Thenuclear magnetic resonance spectrum is consistent with the structureassigned to the product,12-anti-carbomethoxy-10,11-dihydro-5,10-methano-5H-dibenzo-[a,d]cycloheptene.

EXAMPLE 8

The product of Example 7 is mixed with 5 percent sodium hydroxide, andthe mixture is heated on a steam bath for two hours. The mixture ispoured into dilute hydrochloric acid, and the solid product whichprecipitates is separated by filtration. The nuclear magnetic resonancespectrum of the product corresponds to that of the known compound,anti-12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.

EXAMPLE 9

A mixture of 100 ml. of aqueous 10 percent sodium hydroxide and 60 g. of11-acetoxy-syn-carbomethoxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cyclohepteneis stirred with intermittent heating at 50° C. for 23 hours. Diethylether is added, and the layers are separated. The aqueous layer isacidified with hydrochloric acid, the solid product is separated byfiltration and washed with water. The solid product is11-hydroxy-syn-12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.

EXAMPLE 10

The product of Example 9 is mixed with 100 ml. of toluene and 0.2 g. ofp-toluenesulfonic acid. The mixture is heated to its reflux temperatureand maintained at reflux for four hours. The mixture is cooled to about25° C., washed with saturated sodium bicarbonate solution and dried toprovideexo-11-hydroxy-syn-12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo-[a,d]cycloheptenelactone. The structural assignment of the product is confirmed byinfrared and nuclear magnetic resonance spectral analysis.

EXAMPLE 11

To a solution ofexo-11-hydroxy-syn-12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptenelactone (1.4 g.) in ethyl acetate is added 0.5 g. of palladium oncharcoal, and the mixture is treated with hydrogen gas at about 25° C.on a Parr apparatus at about 45 psi. The mixture is filtered thenevaporated under vacuum to provide 1.2 g. of the product,syn-12-carboxy-10,11-dihydro-5,10-methano-5H-dibenzo[a,d]cycloheptene.The structural assignment of the product is confirmed by infrared andnuclear magnetic resonance spectral analysis which are compared to thespectra of the known compound.

EXAMPLE 12

Using the method of Example 3,trans-12-carbomethoxy-11-carboxy-9,10-dihydro-9,10-ethanoanthracene isconverted totrans-11-azido-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene whichis converted totrans-11-(N-carbobenzyloxyamino)-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene,m.p. 138°-140° C.

Analysis: Calculated for C₂₆ H₂₃ NO₄ : %C, 75.4; %H, 5.6; %N, 3.4.Found: %C, 75.5; %H, 5.6; %N, 3.4.

Continuing with the method of Example 3, the intermediate is convertedto trans-11-amino-12-carbomethoxy-9,10-dihydro-9,10-ethanoanthracene. Aportion of the product (5 g.) is dissolved with a mixture of isopropanoland isopropyl ether and is treated with 5 ml. of 8N hydrochloric acid inisopropanol. A white solid precipitates and is collected by filtration.Recrystallization provides the hydrochloride salt, m.p. 260°-262° C.(dec.).

Analysis: Calculated for C₁₈ H₁₇ NO₂ HCl: %C, 68.5; %H, 5.75; %N, 4.44.Found: %C, 68.8; %H, 5.70; %N, 4.30.

The infrared and nuclear magnetic resonance spectra are consistent withthe assigned structure.

What is claimed is:
 1. cis- and trans-11-Amino-12-carbo-lower alkoxy-9,10-dihydro-9,10-ethanoanthracene and acid addition salts thereof.
 2. cis- and trans-11-(N-carbobenzyloxyamino)-12-carbo-lower alkoxy-9,10-dihydro-9,10-ethanoanthracene.
 3. Compound according to claim 1, in which carbo-lower alkoxy is carbomethoxy or carboethoxy.
 4. Compound according to claim 2, in which carbo-lower alkoxy is carboethoxy or carbomethoxy. 